Dominant effects of Δ40p53 on p53 function and melanoma cell fate

Rie Takahashi, Svetomir Nenad Markovic, Heidi J. Scrable

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

The TP53 gene encodes 12 distinct isoforms, some of which can alter p53 activity in the absence of genomic alteration. Endogenous p53 isoforms have been identified in cancers; however, the function of these isoforms remains unclear. In melanoma, the frequency of TP53 mutations is relatively low compared with other cancers, suggesting that these isoforms may have a larger role in regulating TP53 activity. We hypothesized that p53 function and therefore cell fate might be altered by the presence of Δ40p53, an embryonic isoform missing the first 40 N-terminal amino acids of the full-length protein including the transactivation and Mdm2-binding domains. To test this hypothesis, we transduced tumor and normal cells with a lentivirus encoding Δ40p53. We found that exogenous Δ40p53 caused apoptosis and increased the levels of endogenous, activated p53 in both cancerous and non-cancerous cells, which led to significant levels of cell death, particularly in cancer cells. Activated p53 molecules formed nuclear heterotetramers with Δ40p53 and altered downstream p53 transcription target levels including p53-induced protein with death domain and cyclin-dependent kinase inhibitor, p21. Δ40p53 altered the promoter occupancy of these downstream p53 target genes in such a way that it shifted cell fate toward apoptosis and away from cell cycle arrest. We show that tumor suppression by p53 can occur via an alternate route that relies on its interaction with Δ40p53.

Original languageEnglish (US)
Pages (from-to)791-800
Number of pages10
JournalJournal of Investigative Dermatology
Volume134
Issue number3
DOIs
StatePublished - Mar 2014

Fingerprint

Melanoma
Protein Isoforms
p53 Genes
Neoplasms
Tumors
Genes
Cells
Cyclin-Dependent Kinase Inhibitor p21
Apoptosis
Lentivirus
Cell death
Mutation Rate
Transcription
Cell Cycle Checkpoints
Transcriptional Activation
Proteins
Cell Death
Amino Acids
Molecules

ASJC Scopus subject areas

  • Dermatology
  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Dominant effects of Δ40p53 on p53 function and melanoma cell fate. / Takahashi, Rie; Markovic, Svetomir Nenad; Scrable, Heidi J.

In: Journal of Investigative Dermatology, Vol. 134, No. 3, 03.2014, p. 791-800.

Research output: Contribution to journalArticle

@article{4626c4ec6abc47f6a9db907f996e7541,
title = "Dominant effects of Δ40p53 on p53 function and melanoma cell fate",
abstract = "The TP53 gene encodes 12 distinct isoforms, some of which can alter p53 activity in the absence of genomic alteration. Endogenous p53 isoforms have been identified in cancers; however, the function of these isoforms remains unclear. In melanoma, the frequency of TP53 mutations is relatively low compared with other cancers, suggesting that these isoforms may have a larger role in regulating TP53 activity. We hypothesized that p53 function and therefore cell fate might be altered by the presence of Δ40p53, an embryonic isoform missing the first 40 N-terminal amino acids of the full-length protein including the transactivation and Mdm2-binding domains. To test this hypothesis, we transduced tumor and normal cells with a lentivirus encoding Δ40p53. We found that exogenous Δ40p53 caused apoptosis and increased the levels of endogenous, activated p53 in both cancerous and non-cancerous cells, which led to significant levels of cell death, particularly in cancer cells. Activated p53 molecules formed nuclear heterotetramers with Δ40p53 and altered downstream p53 transcription target levels including p53-induced protein with death domain and cyclin-dependent kinase inhibitor, p21. Δ40p53 altered the promoter occupancy of these downstream p53 target genes in such a way that it shifted cell fate toward apoptosis and away from cell cycle arrest. We show that tumor suppression by p53 can occur via an alternate route that relies on its interaction with Δ40p53.",
author = "Rie Takahashi and Markovic, {Svetomir Nenad} and Scrable, {Heidi J.}",
year = "2014",
month = "3",
doi = "10.1038/jid.2013.391",
language = "English (US)",
volume = "134",
pages = "791--800",
journal = "Journal of Investigative Dermatology",
issn = "0022-202X",
publisher = "Nature Publishing Group",
number = "3",

}

TY - JOUR

T1 - Dominant effects of Δ40p53 on p53 function and melanoma cell fate

AU - Takahashi, Rie

AU - Markovic, Svetomir Nenad

AU - Scrable, Heidi J.

PY - 2014/3

Y1 - 2014/3

N2 - The TP53 gene encodes 12 distinct isoforms, some of which can alter p53 activity in the absence of genomic alteration. Endogenous p53 isoforms have been identified in cancers; however, the function of these isoforms remains unclear. In melanoma, the frequency of TP53 mutations is relatively low compared with other cancers, suggesting that these isoforms may have a larger role in regulating TP53 activity. We hypothesized that p53 function and therefore cell fate might be altered by the presence of Δ40p53, an embryonic isoform missing the first 40 N-terminal amino acids of the full-length protein including the transactivation and Mdm2-binding domains. To test this hypothesis, we transduced tumor and normal cells with a lentivirus encoding Δ40p53. We found that exogenous Δ40p53 caused apoptosis and increased the levels of endogenous, activated p53 in both cancerous and non-cancerous cells, which led to significant levels of cell death, particularly in cancer cells. Activated p53 molecules formed nuclear heterotetramers with Δ40p53 and altered downstream p53 transcription target levels including p53-induced protein with death domain and cyclin-dependent kinase inhibitor, p21. Δ40p53 altered the promoter occupancy of these downstream p53 target genes in such a way that it shifted cell fate toward apoptosis and away from cell cycle arrest. We show that tumor suppression by p53 can occur via an alternate route that relies on its interaction with Δ40p53.

AB - The TP53 gene encodes 12 distinct isoforms, some of which can alter p53 activity in the absence of genomic alteration. Endogenous p53 isoforms have been identified in cancers; however, the function of these isoforms remains unclear. In melanoma, the frequency of TP53 mutations is relatively low compared with other cancers, suggesting that these isoforms may have a larger role in regulating TP53 activity. We hypothesized that p53 function and therefore cell fate might be altered by the presence of Δ40p53, an embryonic isoform missing the first 40 N-terminal amino acids of the full-length protein including the transactivation and Mdm2-binding domains. To test this hypothesis, we transduced tumor and normal cells with a lentivirus encoding Δ40p53. We found that exogenous Δ40p53 caused apoptosis and increased the levels of endogenous, activated p53 in both cancerous and non-cancerous cells, which led to significant levels of cell death, particularly in cancer cells. Activated p53 molecules formed nuclear heterotetramers with Δ40p53 and altered downstream p53 transcription target levels including p53-induced protein with death domain and cyclin-dependent kinase inhibitor, p21. Δ40p53 altered the promoter occupancy of these downstream p53 target genes in such a way that it shifted cell fate toward apoptosis and away from cell cycle arrest. We show that tumor suppression by p53 can occur via an alternate route that relies on its interaction with Δ40p53.

UR - http://www.scopus.com/inward/record.url?scp=84894099506&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84894099506&partnerID=8YFLogxK

U2 - 10.1038/jid.2013.391

DO - 10.1038/jid.2013.391

M3 - Article

C2 - 24037342

AN - SCOPUS:84894099506

VL - 134

SP - 791

EP - 800

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

SN - 0022-202X

IS - 3

ER -